P539: A PHASE 1 STUDY OF HMPL-306, A DUAL INHIBITOR OF MUTANT ISOCITRATE DEHYDROGENASE (IDH) 1 AND 2, IN PTS WITH RELAPSED/REFRACTORY MYELOID HEMATOLOGICAL MALIGNANCIES HARBORING IDH1 AND/OR 2 MUTATIONS
Authors: Lijuan Hu, Wei-LI Zhao, Wen Wu, Xudong Wei, Ruihua MI, Yu Hu, Qiubai LI, Wenjuan He, Juan LI, Yugang Dong, Hehua Wang, Xuhan Zhang, Yu Zhang, Zhongyuan Xu, Hui Liu, Zhen Cai, Jie Sun, Yajing Xu, Zhiping Jiang, Cheng Zhang, Guo Chen, Tiejun Gong, Qinghua Tang, Hongmei Jing, Lan MA, Sujun Gao, Qiqi Liu, Zeyu Zhong, Yongxin Ren, Jian Chen, Songhua Fan, Michael Shi, Weiguo Su, Xiaojun Huang
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: HMPL-306 is a potent selective inhibitor of mutant IDH1/2. Aims: The phase 1 study aimed to evaluate safety, tolerability, recommended phase 2 study (RP2D), pharmacokinetics/pharmacodynamics (PK/PD) and preliminary efficacy of HMPL-306 in patients (pts) with relapsed/ refractory myeloid hematological malignancies (HMs) carrying mutant IDH1 and 2. Methods: The open-label, multicenter phase 1 study included dose escalation and dose expansion phases. Pts with relapsed/refractory myeloid HMs carrying mutant IDH1 and/or 2 were eligible. Dose escalation was from 25 mg QD to 250 mg QD in 6 cohorts with 28-day treatment cycles, using mTPI-2 design to determine the maximum tolerated dose (MTD). In dose expansion, pts received HMPL-306 at RP2D in 28-day cycles until disease progression or intolerability toxicity. Primary objectives were safety, tolerability and MTD/RP2D. Secondary objectives mainly included PK/PD and overall response rate (ORR, complete remission [CR]+CR with incomplete hematologic recovery [CRi]+marrow CR [mCR]/ morphologic leukemia-free state+partial remission [PR]). Results: Dose escalation was completed. As of 30 Nov 2022, 49 pts including non-hotspot mutations were enrolled (n=4, 3, 3, 25, 7, 7 in 25, 50, 100, 150, 200, 250 mg QD cohorts, respectively): aged (median) 63 years, 26 pts (53.1%) male, and 31 pts (63.3%) had received ≥2L of prior therapies. No dose-limiting toxicities (DLTs) were observed during DLT observation period. Based on safety, tolerability, PK/PD and preliminary efficacy in each cohort, 30 additional pts were enrolled in 150 (n=22), 200 (n=4) and 250 (n=4) mg QD cohorts. The best of response was 1 CR in 100 mg cohort; 9 CRs (CR+CRi, including 5 CRminimal residual disease negative [MRD-]) and 1 PR in 150 mg QD; 1 CR in 200 mg QD; and 3 CRs (CR+CRi, including 1 CRMRD-) in 250 mg QD; with an ORR of 33.3% (1/3), 40.0% (10/25), 14.3% (1/7) and 42.9% (3/7), respectively. Of pts with susceptible IDH1 and 2 mutations (IDH1-R132C, IDH2-R140Q or R172K) (n=37), the ORR was 50.0% (1/2), 45.0% (9/20), 25.0% (2/4) and 50.0% (3/6) in 100, 150, 200 and 250 mg QD cohorts, respectively. Drug exposures in plasma were increased with dose from 25 mg to 250 mg. Mean terminal t1/2 was 90-120 h, and the steady state was reached after 22 or 28 days with about 5-fold accumulation following multiple doses. Target inhibition indexed with plasma 2-HG level change was influenced by IDH mutation types and 2-HG baselines of subjects. After balancing baselines, 250 mg QD was predicted to achieve >90% target inhibition much earlier than 150 mg QD, and the maximum target inhibition after multiple doses of 250 mg QD was slightly higher than 150 mg. 34 (69.4%) pts reported TRAEs, and 13 (26.5%) pts reported grade ≥3 TRAEs. The safety profile was similar in 150 and 250 mg QD cohorts during all treatment cycles, and 250 mg QD showed a favorable non-hematological toxicities over 150 mg QD in Cycle 1. Summary/Conclusion: Combing with safety, tolerability, PK/PD and preliminary efficacy, the RP2D was set as 250 mg QD at Cycle 1, and then with 150 mg QD from Cycle 2. Dose expansion is ongoing. Clinical trial information: NCT04272957. Keywords: Myeloid malignancies, Hematological malignancy